The biosynthesis of a wide range of industrially interesting natural products in engineered host cells (so called cell factories) could tap the unrealized commercial potential of these natural resources. Thus, there is growing interest in developing platform cell factories that can efficiently convert cheap sources of carbon into so-called precursor metabolites that are then further converted into the product of interest. One of these key metabolites is acetyl-CoA that is used as precursor for the production of a wide range of industrially interesting products including isoprenoids (mainly used as flavours and fragrances, biodiesels, antimalarial and anticancer drugs, antibiotics, rubber, dietary supplements, food ingredients and vitamins), polyketides (antibiotics, anticancer drugs and immunosuppressors), lipids (such as dietary supplements, pharmaceuticals and biodiesels), polyhydroxyalkanoates and 1-butanol (FIG. 1).
In a former study, engineering of the pyruvate dehydrogenase bypass in Saccharomyces cerevisiae was shown to enhance the supply of acetyl-CoA and to increase the production of the sesquiterpene compound amorphadiene (Metab Eng 2007, 9:160; WO 2007024718). This was achieved by over-production of an acetaldehyde dehydrogenase and introduction of an heterologous Salmonella enterica acetyl-CoA synthetase variant into the host cell.
However, there remains a need to further increase the acetyl-CoA production, which when met should increase production of any desired acetyl-CoA derived product. The present invention addresses this issue using a combined push-pull-block strategy, thus providing a platform cell factory that can be used to improve the production of acetyl-CoA derived products. This is exemplified using three different compounds derived from acetyl-CoA.